Why Did so Few of my Eggs Fertilize into Embryos, and so Many More Fail to Reach Blastocyst?

One of the most common questions asked by patients undergoing IVF relates to the likelihood of their eggs fertilizing and the likely “quality” of their embryos. This is also one of the most difficult questions to answer. On the one hand many factors that profoundly influence egg quality; such as the genetic recruitment of eggs for use in an upcoming cycle, the woman’s age and her ovarian reserve, are our outside of our control.

On the other hand the protocol for controlled ovarian stimulation (COS) can also profoundly influence egg/embryo development and this is indeed chosen by the treating physician.

First, it should be understood that the most important determinant of fertilization potential, embryo development and blastocyst generation, is “competency” of the embryo that is mostly affected by the numerical chromosomal integrity (ploidy) of the egg. While sperm quality does play a role, in the absence of moderate to severe sperm dysfunction this is (moderate or severe male factor infertility a relatively small one). Human eggs have the highest rate of numerical chromosomal irregularities (aneuploidy) of all mammals. In fact only about half the eggs of women in their twenties or early thirties, have the required number of chromosomes (euploid), without which upon fertilization they cannot propagate a normal pregnancy. As the woman advances into and beyond her mid-thirties, the percentage of eggs euploid eggs declines progressively such that by the age of 40 years, only about one out of six are likely to be chromosomally normal. By her mid-only about forties one in ten of her eggs will be euploid and by 4r years of age, fewer than one in twenty will be euploid.

Second; embryos that fail to develop into blastocysts are almost always aneuploid and not worthy of being transferred to the uterus because they will either not implant, will miscarry or could even result in a chromosomally abnormal baby (e.g. Down syndrome). However, it is incorrect to assume that all embryos reaching the blastocyst stage are will be euploid (“competent”). It is true that since many aneuploid embryos are lost during development and that those failing to survive to the blastocyst stage are far more likely to be competent than are earlier (cleaved) embryos.  What is also true is that the older the woman who produced the eggs, the less likely it is that a given blastocyst will be “competent”. As an example, a morphologically pristine blastocyst derived from the egg of a 30 year old woman would have about a 50:50 chance of being euploid and such a microscopically normal embryo would have 25%-30% chance of propagating a healthy, normal baby, while a microscopically comparable blastocyst derived through fertilization of the eggs from a 40 year old, would be about half as likely to be euploid and/or propagate a healthy baby and by 45 years of age – less than 5%. . While the effect of species on the potential of eggs to be euploid at ovulation is genetically preordained and nothing we do can alter this equation, there is unfortunately a lot we can (often unwittingly) do to worsen the situation by selecting a suboptimal protocol of controlled ovarian stimulation (COS). This, by creating an adverse intraovarian hormonal environment will often disrupt normal egg development and lead to a higher incidence of egg aneuploidy than otherwise might have occurred.  Older women, women with diminished ovarian reserve (DOR) and those with polycystic ovarian syndrome are especially vulnerable in this regard. During the normal, ovulation cycle, ovarian hormonal changes are regulated to avoid irregularities in production and interaction that could adversely influence follicle development and egg quality. As an example, small amounts of androgens (male hormones such as testosterone), that are produced by the ovarian stroma (tissue surrounding ovarian follicles) during the pre-ovulatory phase of the cycle enhance late follicle development, estrogen production by the granulosa cells (that line the inner walls of follicles), and egg maturation. However, over-production of testosterone can adversely influence the same processes. It follows that COS protocols should be individualized and geared toward optimizing follicle growth and development time while avoiding excessive ovarian androgen (testosterone) production and that the hCG “trigger shot” should be carefully timed. In summary it is important to understand the influence species, age of the woman as well as the effect of the protocol used for ovarian stimulation, on the chromosomal integrity of the egg (“competency) on, fertilization potential, blastocyst generation, and thus on IVF outcome. With the exception of, the hormonal ovarian environment created by the protocol used for ovarian stimulation, all other factors are inherent and unavoidable. This is why selection of the protocol used for ovarian stimulation is by far the most important decision that the RE has to make when it comes to trying to influence IVF outcome. This becomes even more relevant when dealing with older women, those with DOR and women with polycystic ovarian syndrome (PCOS) who are the most vulnerable in this regard.